Referencia

Miguel V, Tituaña J, Herrero JI, Herrero L, Serra D, Cuevas P, Barbas C, Puyol DR, Márquez-Expósito L, Ruiz-Ortega M, Castillo C, Sheng X, Susztak K, Ruiz-Canela M, Salas-Salvadó J, González MAM, Ortega S, Ramos R, Lamas S. Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J Clin Invest. 2021 Mar 1;131(5):e140695. doi: 10.1172/JCI140695. PMID: 33465052; PMCID: PMC7919728.
Portada JCI

Autores

Verónica Miguel, Jessica Tituaña, J Ignacio Herrero, Laura Herrero, Dolors Serra, Paula Cuevas, Coral Barbas, Diego Rodríguez Puyol, Laura Márquez-Expósito, Marta Ruiz-Ortega, Carolina Castillo, Xin Sheng, Katalin Susztak, Miguel Ruiz-Canela, Jordi Salas-Salvadó, Miguel A Martínez González, Sagrario Ortega, Ricardo Ramos, Santiago Lamas

Resumen

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

Descripción

En este trabajo hemos estudiado cómo la mejora de la capacidad energética de las células epiteliales tubulares renales protege al riñón de la fibrosis. Mediante la sobre-expresión de una proteína enzimática mitocondrial, Cpt1a, que permite que los ácidos grasos de cadena larga puedan entrar en las mitocondrias, hemos observado en diferentes modelos experimentales de fibrosis, que existe una protección significativa frente al desarrollo de fibrosis. El metabolismo de los ácidos grasos dentro de la mitocondria confiere un gran poder bioenergético, al generar una gran cantidad de ATP y mantener a las células epiteliales en un estado óptimo para defenderse de la inflamación crónica, origen principal de la fibrosis.

Imagen del grupo SLamas

REFERENCIA DEL GRUPO INVESTIGADOR

El laboratorio dirigido por el Dr. Santiago Lamas en el Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM) está interesado en los mecanismos moleculares que subyacen al proceso de fibrogénesis en patología humana, que implica el reemplazo de tejido vivo celular por matriz extracelular, con el posterior trastorno funcional. Durante los últimos años nos hemos centrado en la fibrosis renal en relación con dos preguntas: a) el papel del metabolismo oxidativo en la génesis de la lesión y reparación renal y b) el papel de miRNAs involucrados en rutas metabólicas críticas para la función de las células epiteliales tubulares. Nuestro objetivo es prevenir, diferir o revertir la fibrosis en el riñón mediante el conocimiento de los cambios metabólicos subyacentes asociados a la fibrosis renal.

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